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WO2018099451A1 - Forme cristalline d'un composé - Google Patents

Forme cristalline d'un composé Download PDF

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Publication number
WO2018099451A1
WO2018099451A1 PCT/CN2017/114194 CN2017114194W WO2018099451A1 WO 2018099451 A1 WO2018099451 A1 WO 2018099451A1 CN 2017114194 W CN2017114194 W CN 2017114194W WO 2018099451 A1 WO2018099451 A1 WO 2018099451A1
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WIPO (PCT)
Prior art keywords
cancer
degrees
compound
formula
solvent
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Ceased
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PCT/CN2017/114194
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English (en)
Chinese (zh)
Inventor
吴振平
李文姬
储玉平
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Hutchmed Ltd
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Hutchison Medipharma Ltd
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Priority to CN201780074441.8A priority Critical patent/CN110023318A/zh
Publication of WO2018099451A1 publication Critical patent/WO2018099451A1/fr
Anticipated expiration legal-status Critical
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention belongs to the field of pharmacy and provides the compound (3aR,6aR)-N-(4-(3-ethynylphenylamino)-7-methoxyquinazolin-6-yl)-1-methyl-hexahydro
  • epidermal growth factor (EGF)
  • EGFR epidermal growth factor receptor
  • Overexpression and/or overactivation of EGFR can lead to uncontrolled cell division, and uncontrolled cell division can be a cause of cancer.
  • compounds that inhibit EGFR overexpression and/or overactivation are candidates for treating tumors.
  • Patent CN102906086A discloses the compound (3aR,6aR)-N-(4-(3-ethynylphenylamino)-7-methoxyquinazolin-6-yl)-1-methyl-hexahydropyrrolo[3 , 4-b]pyrrole-5(1H)-carboxamide and a process for the preparation thereof.
  • the invention provides (3aR,6aR)-N-(4-(3-ethynylphenylamino)-7-methoxyquinazolin-6-yl)-1-methyl-hexahydropyrrole Form I crystal of [3,4-b]pyrrole-5(1H)-carboxamide, Form I of the compound of formula A.
  • Form I of the compound of formula A provided by the present invention has good crystallinity, non-hygroscopicity and stability characteristics, and has acceptable oral bioavailability.
  • the invention provides a process for the preparation of Form I of a compound of formula A which is reproducible and easy to handle.
  • the invention provides a pharmaceutical composition comprising an effective amount of Form I of a compound of Formula A, and the balance of at least one pharmaceutically acceptable carrier.
  • the invention also provides a method of treating cancer that has an effect on inhibiting epidermal growth factor receptor overexpression and/or overactivity.
  • the method comprises administering to a subject in need thereof an effective amount of Form I of a compound of Formula A.
  • the invention also provides the use of Form I of a compound of formula A for the manufacture of a medicament for the treatment of a cancer, such as lung cancer, head and neck cancer, which has an effect on inhibiting the overexpression and/or overactivity of the epidermal growth factor receptor, Colorectal cancer, pharyngeal cancer, epidermoid carcinoma and pancreatic cancer.
  • a cancer such as lung cancer, head and neck cancer
  • Figure 1 shows a powder X-ray diffraction pattern of Form I of the compound of Formula A, with the horizontal axis (X-axis) being the diffraction angle 2 ⁇ and the vertical axis (Y-axis) being the diffraction intensity.
  • Figure 2 shows a differential scanning calorimetry diagram of Form I of the compound of Formula A, with the horizontal axis (X-axis) being the temperature and the vertical axis (Y-axis) being the heat flow.
  • Figure 3 is a graph showing the thermogravimetric analysis of Form I of the compound of Formula A, with the horizontal axis (X-axis) being the temperature and the vertical axis (Y-axis) being the weight percent.
  • crystalline form of the invention refers to crystalline form I of the compound of formula A.
  • compound of formula A or "(3aR,6aR)-N-(4-(3-ethynylphenylamino)-7-" Methoxyquinazolin-6-yl)-1-methyl-hexahydropyrrolo[3,4-b]pyrrole-5(1H)-carboxamide refers to a compound having the chemical structure of formula A below (also Can be called compound A):
  • C1-6 alkyl alcohol refers to a fully saturated linear or branched alkyl alcohol having 1, 2, 3, 4, 5 or 6 carbon atoms. Examples thereof include, but are not limited to, methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, n-pentanol, isoamyl alcohol, n-hexanol, and the like.
  • halogenated alkane having less than three carbon atoms means a fully saturated hydrocarbon having 1 or 2 carbon atoms which is substituted by one or more halogen atoms selected from F, Cl, Br or I. Examples thereof include dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, and the like.
  • solution refers to a mixture of one or more solutes in one or several solvents for a particular use.
  • solution is meant a homogeneous mixture, and a multi-phase mixture, such as a beater or other suspension mixture containing insolubles.
  • organic solvent refers broadly to any suitable organic solvent for a particular use herein.
  • solvent means any suitable organic solvent which can partially or completely dissolve the solute under suitable conditions, such as a suitable amount, a suitable temperature, such as room temperature or elevated temperature.
  • anti-solvent solvent refers to any suitable organic solvent in which the solubility of the material is less than the solubility in the dissolved solvent.
  • an "effective amount" of a compound of formula A and a crystalline form of a compound of formula A which refers to a dose administered to a patient
  • the amount of the drug in this amount, can effectively alleviate and improve a certain cancer that inhibits the overexpression and/or excessive activity of the epidermal growth factor receptor, and the individual can be a human or an animal.
  • the cancer in which the inhibition of epidermal growth factor receptor overexpression and/or excessive activity is inhibited may be, but not limited to, lung cancer, head and neck cancer, colorectal cancer, pharyngeal cancer, epidermoid carcinoma, and pancreatic cancer.
  • the "effective amount” will vary depending on the compound, the condition being treated, the severity of the condition being treated, the age and associated condition of the individual, the route and form of administration, the judgment of the attending physician or the veterinary practitioner, and the like. .
  • mammals means both mammalian and non-mammal.
  • Mammal means any member of the mammalian class including, but not limited to, humans; non-human primates such as chimpanzees and other apes and monkeys; farm animals such as cattle, horses, sheep, goats and pigs; domestic animals such as rabbits , dogs and cats; laboratory animals, including rodents such as rats, mice and guinea pigs; Examples of non-mammals include, but are not limited to, birds and the like.
  • the term "individual” does not mean a particular age or gender.
  • the present invention provides the compound (3aR,6aR)-N-(4-(3-ethynylphenylamino)-7-methoxyquinazolin-6-yl)-1-methyl-hexahydropyrrolo[3 , a new crystalline form of 4-b]pyrrole-5(1H)-carboxamide.
  • the crystalline form I of the present invention has the characteristics of good crystallinity, non-hygroscopicity and stability, and has acceptable oral bioavailability, and is suitable for preparation of an oral pharmaceutical preparation.
  • the reproducibility of the crystalline form I of the present invention is good, and reproducible amplification can be carried out to produce the crystalline form I; and it is stable in a common preparation, thereby facilitating the production of a preparation and use in the treatment of a disease.
  • the crystal form I of the present invention has high purity; less solvent residue, which meets the requirements for the quality of the drug substance, such as the requirement of ICH Q3A.
  • the crystalline form of the invention can be carried out by one or several solid state analytical methods Identification.
  • the crystalline form of the present invention can be carried out by one or more methods such as powder X-ray diffraction, single crystal lattice parameters, Fourier infrared spectroscopy, differential scanning calorimetry data, and/or thermogravimetric curves. Identification. And if the result of the discrimination analysis of one of the methods is consistent with the crystal form of the present invention, it does not mean that the identification result of any of the other methods is inconsistent with the crystal form of the present invention.
  • the new crystal form can be identified by powder X-ray diffraction spectroscopy.
  • the peak intensities and/or peak conditions of powder X-ray diffraction may vary depending on experimental conditions, such as different diffraction test conditions and/or orientation preferences.
  • the measured 2 ⁇ value will have an error of about ⁇ 0.2 2 ⁇ .
  • the relative intensity value of the peak is more dependent on the properties of the sample than the position of the peak, such as the size of the crystal in the sample, the orientation of the crystal, and the purity of the material being analyzed, thus the peaks thus displayed.
  • a strength deviation of about ⁇ 20% or more is possible.
  • those skilled in the art can obtain sufficient information for discriminating the crystal form I from the XRPD data provided in this patent.
  • the present invention provides Form I of the compound of Formula A.
  • Form I of the compound of Formula A can be identified by X-ray powder diffraction.
  • the powder X-ray diffraction characteristic diffraction angle (2 ⁇ ) of Form I of the compound of Formula A is 5.4 degrees, 6.5 degrees, 10.1 degrees, 12.2 degrees, 13.1 degrees, 16.2 degrees, and the measured 2 ⁇ values are An error of about ⁇ 0.2 2 ⁇ .
  • the powder X-ray diffraction characteristic diffraction angle (2 ⁇ ) of Form I is 5.4 degrees, 6.5 degrees, 8.0 degrees, 10.1 degrees, 10.8 degrees, 12.2 degrees, 13.1 degrees, 14.8 degrees, 16.2 degrees, 22.6. Degree, 25.4 degrees, the measured 2 ⁇ value has an error of about ⁇ 0.2 2 ⁇ .
  • powder X-ray diffraction characteristic diffraction of Form I of a compound of Formula A The angles (2 ⁇ ) are 5.4 degrees, 6.5 degrees, 8.0 degrees, 10.1 degrees, 10.8 degrees, 12.0 degrees, 12.2 degrees, 13.1 degrees, 14.8 degrees, 16.2 degrees, 17.3 degrees, 18.1 degrees, 20.5 degrees, 22.6 degrees, 23.1 degrees, At 25.4 degrees and 26.6 degrees, the measured 2 ⁇ value has an error of about ⁇ 0.2 2 ⁇ .
  • the powder X-ray diffraction characteristic diffraction angle (2 ⁇ ) of Form I of the compound of Formula A is 5.4 degrees, 6.5 degrees, 8.0 degrees, 10.1 degrees, 10.8 degrees, 12.0 degrees, 12.2 degrees, 13.1 degrees, 14.8 degrees, 16.2 degrees, 17.3 degrees, 18.1 degrees, 18.8 degrees, 20.5 degrees, 21.1 degrees, 22.6 degrees, 23.1 degrees, 24.1 degrees, 25.4 degrees, 26.6 degrees, 27.2 degrees, and the measured 2 ⁇ values have about ⁇ 0.2 2 ⁇ . error.
  • the powder X-ray diffraction characteristic diffraction angle (2 ⁇ ) of Form I of the compound of Formula A is 5.4 degrees, 6.5 degrees, 8.0 degrees, 10.1 degrees, 10.8 degrees, 12.0 degrees, 12.2 degrees, 13.1 degrees, 14.4, 14.8, 16.2, 17.3, 18.1, 18.8, 20.5, 21.1, 22.6, 23.1, 24.1, 25.4, 26.6, 27.2, 29.9, 30.7.
  • the measured 2 ⁇ value has an error of about ⁇ 0.2 2 ⁇ .
  • Form I of the compound of Formula A has a diffraction pattern as shown in FIG. Those skilled in the art can obtain sufficient information for identifying Form I of the compound of Formula A from the XRPD data provided in this patent, despite experimental error, instrumental error, and orientation preference.
  • Form I of the compound of Formula A can be identified by differential scanning calorimetry. In some embodiments, Form I of the compound of Formula A has a differential scanning calorimetry curve as shown in FIG. In the DSC spectrum, the endothermic peak of Form I of the compound of Formula A is between about 259.4 and 261.7 °C.
  • Form I of the compound of Formula A can be identified by thermogravimetric analysis.
  • Form I of the compound of Formula A has a thermogravimetric analysis curve as shown in Figure 3, which shows that Form I is an anhydride or a pure crystal.
  • the compound of formula A has a Form I weight content of at least 99%, At least 95%, at least 90%, or as low as 80%. Still alternatively, the crystalline form I compound has a Form I weight content of at least 70%, or at least 60%. Further or more, the compound of formula A has a Form I weight content of at least 50%.
  • This patent relates to a process for the preparation of Form I of a compound of formula A, comprising:
  • the compound (3aR,6aR)-N-(4-(3-ethynylphenylamino)-7-methoxyquinazolin-6-yl)-1- Methyl-hexahydropyrrolo[3,4-b]pyrrole-5(1H)-carboxamide is preferably a solid, such as a single crystal form, such as Form I, or two or more crystal forms. mixture.
  • the compound (3aR, 6aR)-N-(4-(3-ethynylphenylamino)-7-methoxyquinazolin-6-yl)-1 -Methyl-hexahydropyrrolo[3,4-b]pyrrole-5(1H)-carboxamide is not completely dissolved in the suspension system, i.e., some of the compounds are present in solid form.
  • the water-miscible organic solvent accounts for a volume of the mixed solvent.
  • the score is less than about 95%.
  • the water miscible organic solvent is selected from the group consisting of acetone, methanol, ethanol, isopropanol, tetrahydrofuran, N,N-dimethylacetamide, and acetonitrile.
  • the selected water-miscible organic solvent is ethanol, the volume percentage of ethanol is not less than about 10%.
  • the water miscible organic solvent and water are mixed in a suitable ratio.
  • the volume ratio of water-miscible organic solvent to water is from about 9:1 to about 1:9, or about 1:1, such as ethanol/water (volume ratio is from about 9:1 to about 1:9) ).
  • the suspension in the step (2), may be heated while stirring, and the heating temperature should be no higher than the boiling point of the solvent system, for example, about 40 degrees, about 60 degrees, and about 80 degrees.
  • the heating can promote the conversion of the solid in the suspension system to Form I of the compound of Formula A.
  • the suspension in the step (2), may be stirred for a period of 20 to 100 hours, such as at least 24 hours, at least 48 hours, at least 60 hours, and at least 72 hours.
  • This patent relates to another method of preparing Form I of a compound of Formula A, comprising:
  • the dissolving solvent is selected from the group consisting of N,N-dimethylformamide or N,N- Dimethylacetamide.
  • the reverse dissolution solvent is selected from the group consisting of acetonitrile.
  • the volume ratio of the dissolving solvent to the anti-solvent solvent is from about 1:10 to about 5:1, such as 0.3/1.
  • compositions and methods of treatment are provided.
  • Form I of the compound of formula A can be used in the treatment of diseases such as cancer.
  • the cancer includes, but is not limited to, lung cancer, head and neck cancer, colon cancer, pancreatic cancer, colon cancer, breast cancer, ovarian cancer, prostate cancer, stomach cancer, kidney cancer, liver cancer, brain cancer, esophageal cancer, bone cancer and sarcoma, such as Soft tissue sarcoma, as well as leukemia.
  • compositions of formula A comprising administering an active pharmaceutical ingredient formed from a compound of formula A, or a pharmaceutically acceptable salt thereof, or Form I of the inventive compound of formula A.
  • such a method of treatment is directed to at least one method of inhibiting epidermal growth factor receptor overexpression and/or overactivation, such as cancer.
  • an effective amount of a pharmaceutical composition of the invention is administered to an individual in need thereof, the pharmaceutical composition comprising at least one pharmaceutically acceptable carrier, and Form I of the compound of Formula A.
  • the amount of the at least one active pharmaceutical ingredient selected from the compound of the formula A and/or a pharmaceutically acceptable salt thereof, or the crystalline form I of the compound of the formula A to achieve the desired physiological effect depends on various factors, for example, the purpose of use, The mode of administration, as well as the clinical condition of the patient.
  • the daily dose may be, for example For example, ranging from 0.01 mg to 3 g per day (eg, from 0.05 mg to 2 g per day, or even from 100 mg to 1 g per day).
  • Unit dosage formulations which can be administered orally include, for example, tablets or capsules.
  • Form I of the compound of Formula A can be administered in the form of the compound itself, but usually they are used in the form of a pharmaceutical composition in combination with one or more pharmaceutically acceptable carriers or excipients. .
  • a representative carrier or excipient should be compatible with the other ingredients of the composition and will not compromise the health of the patient.
  • the carrier or excipient may be either solid or liquid, or both, in combination with Form I of the compound of Formula A, in a pharmaceutical composition or unit dosage form (eg, tablet, capsule), which may contain 0.05% by weight. Up to 95% of the compound of formula A.
  • the pharmaceutical compositions described in the present invention can be prepared by known pharmaceutical preparation methods, for example, by mixing with a pharmaceutically acceptable carrier and/or adjuvants and diluents, and the like.
  • representative carriers or adjuvants include, but are not limited to, microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, calcium hydrogen phosphate, glycine, disintegrants such as starch, croscarmellose sodium. , complex silicates and high molecular weight polyethylene glycols, granulating binders (such as polyvinylpyrrolidone, sucrose, gelatin, gum arabic), and lubricants (such as magnesium stearate, glycerin and talc).
  • microcrystalline cellulose lactose, sodium citrate, calcium carbonate, calcium hydrogen phosphate, glycine
  • disintegrants such as starch, croscarmellose sodium.
  • complex silicates and high molecular weight polyethylene glycols such as polyvinylpyrrolidone, sucrose, gelatin, gum arabic
  • lubricants such as magnesium stearate, glycerin and talc
  • Form I of the compound of Formula A can be combined with at least one component, such as a carrier and/or adjuvant and/or diluent, which can be selected from sweeteners, flavoring agents. , colorants, dyes and emulsifiers.
  • a carrier and/or adjuvant and/or diluent which can be selected from sweeteners, flavoring agents. , colorants, dyes and emulsifiers.
  • Form I of the compound of Formula A does not undergo conversion when formulated with one or more pharmaceutically acceptable carriers and/or adjuvants and/or diluents.
  • Form I of the compound of Formula A may be converted, when formulated in one or more pharmaceutically acceptable carriers and/or adjuvants and/or diluents, in whole or in part converted to a One or more crystalline forms, including conversion to a non-solid form.
  • Exemplary carriers and/or adjuvants and/or diluents include, but are not limited to, water, Ethanol, propylene glycol, glycerin, and mixtures thereof.
  • Form I of the present invention can be dissolved when formulated into a pharmaceutical composition. Thus, in these "dissolved” examples, Form I is no longer present in crystalline form in the pharmaceutical composition.
  • Form I of the compound of Formula A is administered in a suitable formulation.
  • compositions described herein may be those which are suitable for oral and oral (e.g. sublingual) administration, and the appropriate mode of administration may depend on the condition of each case and the severity of the treatment. It also depends on the nature of the particular form of Form I of the compound of Formula A used in the preparation of a pharmaceutical composition.
  • the pharmaceutical compositions described herein may also be in the form of a coated dosage form and a coated sustained release dosage form. Acidic and anti-gastric dosage forms are also possible. Suitable anti-gastric coating materials include cellulose acetate phthalate, polyvinyl acetate phthalic acid, cellulose hydroxypropyl methyl phthalate, anionic polymers of methacrylic acid, methyl methacrylate .
  • Suitable pharmaceutical compositions for oral administration from Form I of the compound of formula A may also be in unit dosage form, for example, capsules, cachets and tablets, including suckable tablets, each consisting of At least one active pharmaceutical ingredient of the invention is prepared quantitatively; the formulation may also be selected from powders, granules, solutions, suspensions in water or non-aqueous liquids, oil-in-water and water-in-oil emulsions. These compositions may also be prepared as described above by any suitable pharmaceutical formulation, for example, including the following steps: Form I of the compound of Formula A, and carriers and/or adjuvants and/or diluents (optional) One or more of the added ingredients are combined). These compositions are generally prepared by uniformly and homogeneously mixing Form I of the compound of Formula A with a liquid or a finely divided solid carrier, the product of which may be shaped.
  • compositions of the invention may be administered topically or systemically.
  • compositions suitable for oral (including sublingual) administration can be made into a formable tablet comprising Form I of the compound of Formula A and a flavoring agent.
  • Flavoring agents are typically selected from the group consisting of sucrose, gum arabic, tragacanth, and the like.
  • compositions of the present invention may also be those which can be administered parenterally, such as inhalation sprays, or implantable reservoirs.
  • Solid carriers for use therein include, for example, starch, lactose, microcrystalline cellulose, aluminosilicates, and any suitable ingredients.
  • Liquid carriers include, for example, water for injection, polyvinyl alcohol, nonionic surfactants, and corn oil, as well as any suitable ingredients.
  • Other commonly used pharmaceutical formulation excipients include coloring agents, preservatives, flavoring agents, and antioxidants such as vitamin E, vitamin A, BHT, and BHA.
  • Form I of the compound of formula A according to the invention may also be administered intraperitoneally.
  • Solutions and suspensions of the compounds can be prepared by dissolving or suspending these compounds in water containing the surfactant.
  • Dispersed suspensions may be prepared from glycerol, polyethylene glycol (PEG) or mixtures thereof with a suitable oil.
  • Preservative ingredients can be added to these formulations to prevent the growth of microorganisms during use.
  • Injectable formulations include non-toxic aqueous solutions or suspensions and non-toxic powders. In all of these cases, these dosage forms must be non-toxic, easily transferable from the syringe, stable under the conditions of manufacture and storage, and free from contamination and microbial infections.
  • the carrier can be a solvent or dispersing agent, including water, alcohol, and some suitable oils.
  • Form I of the compound of formula A can also be used in combination with one or more other active ingredients (e.g., in a synergistic treatment).
  • the active ingredients may be separate compositions for simultaneous administration by the same or different routes of administration in therapy or separately (eg, sequentially administered in any order) at different times, or they may be the same
  • the pharmaceutical compositions are administered together.
  • Form I of a compound of Formula A can be administered concurrently with one or more other active ingredients known to have therapeutic effects, such as for treatment of inhibition of epidermal growth factor receptor overexpression and/or overactivity.
  • Affected diseases such as cancer.
  • anti-tumor method May refer to any method for the treatment of cancer.
  • anti-tumor methods include, but are not limited to, radiotherapy, immunotherapy, chemotherapy for DNA damage, and chemotherapy for disrupting cell replication.
  • topoisomerase I inhibitors eg, irinotecan, topotecan, camptothecin, and analogs or metabolites thereof
  • Topoisomerase II inhibitors eg, etoposide, teniposide, daunorubicin
  • alkylating agents eg, melphalan, chlorambucil, busulfan, thiotepa, Cyclophosphamide, carmustine, lomustine, semustine, streptozotocin, dacarbazine, methotrexate, mitomycin, cyclophosphamide
  • DNA intercalators eg, cis Platinum, oxaliplatin and carboplatin; DNA intercalators and free radical generators such as bleomycin; and nucleoside analogues (eg 5-fluorouracil, capecitabine, gemcitabine, fludarabine, Cytara
  • Chemotherapy drugs that disrupt cell replication including but not limited to: paclitaxel, docetaxel, and related analogs; vincristine, vinblastine, related analogs; thalidomide and related analogs (eg, CC-5013 and CC-) 4047); protein tyrosine kinase inhibitors (eg, imatinib mesylate, furazolinib, and gefitinib); protease inhibitors (eg, bortezomib); inhibitors of NF- ⁇ B, Kinase inhibitors including I ⁇ B; antibodies that bind to overexpressed proteins in cancer, which can downregulate cell replication (eg, rituximab, cetuximab, bevacizumab, etc.); other known in cancer An inhibitor of a protein or enzyme that is up-regulated or over-expressed or activated, which can down-regulate cell replication by inhibiting these proteins or enzymes.
  • the methods described herein are not limited to the order of administration, and one or more additional active ingredients may be administered either simultaneously or after administration or administration.
  • the starting material of the compound of formula A used in the examples was prepared according to CN102906086A.
  • Differential scanning calorimetry analysis is measured by a DSC 7 from Perkin Elmer (purge gas: nitrogen, flow rate: 50mL min -1, temperature rise rate: 5-10 °C / min, measuring range: 25 °C ⁇ 200 °C) measured sample
  • the measurement used a rolled aluminum pan and temperature correction using indium.
  • Thermogravimetric analysis was determined by Perkin Elmer's TGA7 (purge gas: nitrogen, flow rate: 50 mL min-1, temperature increase rate: 10 ° C/min).
  • Solvent condition result Solvent usage (volume/mass ratio) Methanol 50 ° C / 3 days Crystal form I 10 times Ethanol 50 ° C / 3 days Crystal form I 10 times Isopropanol 50 ° C / 3 days Crystal form I 10 times Tetrahydrofuran 50 ° C / 3 days Crystal form I 10 times Dichloromethane 50 ° C / 3 days Crystal form I 10 times acetone 50 ° C / 3 days Crystal form I 10 times Butanone 50 ° C / 3 days Crystal form I 10 times Acetonitrile 50 ° C / 3 days Crystal form I 10 times Toluene 50 ° C / 3 days Crystal form I 10 times Ethanol/water (9:1, V/V) Room temperature / 66 hours Crystal form I 30 times
  • Determination method The test sample of the formula I of the compound of the formula A prepared by the above examples was weighed and placed in a petri dish, and the opening was placed in a sealed clean container at a temperature of 60 ° C, 25 ° C and relative humidity, respectively. After being placed for 92 days at 92.5% ⁇ 5% and illuminance at 4500lx ⁇ 500lx, sampling, the purity of the sample (using HPLC analysis) and the crystal form (using X-ray powder diffraction analysis) were investigated, and the results were compared. The results are shown in Table 3.
  • Determination method Weigh two samples of the crystal form I prepared by the foregoing examples, placed in two Petri dishes, respectively, and the exposed openings were placed in a sealed clean container having a relative humidity of 92.5% and 75%, room temperature. After 10 days under the test, the sample weight was weighed and placed for 10 days, and the moisture absorption weight percentage and crystal form (using X-ray powder diffraction analysis) of the sample were calculated in comparison with the sample weight before the start of the test. The results are shown in Table 4.
  • Form I is placed under high humidity conditions for 10 days, and the moisture absorption gain is only 0.01%.
  • Form I is non-hygroscopic. During the placement process, the crystal form does not change. Form I is stable.
  • a compound of formula A prepared by the foregoing examples, which is Form I, has a purity of 98.5%.
  • HS 15 polyethylene glycol stearate
  • Preparation of intravenous administration solution of compound of formula A warm water heating HS 15, after the fluidity became better, take 22.5 mL, add 22.5 mL of physiological saline, vortex and mix it evenly, and prepare a mixture solution of Solutol and physiological saline (volume ratio 1:1) for use.
  • the crystalline form I of the compound of formula A was weighed 108.47 mg, 1.06 mL of DMSO was added, 90 ⁇ L of 12 M HCl was added, and vortexed to obtain a yellow clear transparent solution.
  • HS 15 and saline mixed solution (volume ratio of 1:1) 42.6mL, vortex 1min, ultrasound for 2min, add physiological saline to 212.8mL, for intravenous injection.
  • the final intravenous preparation is 10% Physiological saline solution of HS 15, 0.5% DMSO and 0.04% 12 M HCl.
  • Formulation for Oral Administration of Compound A of Formula A According to the body weight of the animal and the dose to be administered, an appropriate amount of the compound I of the formula A is weighed and filled into a capsule for human (CAPSUGEL, Lot#: 12832590), a dog Give a capsule.
  • 6 beagle dogs, half male and half female. Dosing was administered in 4 experimental cycles, self-control.
  • the first, second and third cycles are oral administration of 1.0, 2.5 and 7.5 mg/kg for single administration (the above-mentioned formulated oral administration preparation), and the fourth period is intravenous administration of 1.0 mg/kg for single administration (the above preparation) Intravenous preparation).
  • the cleaning period during the week is one week. Animals were fasted overnight before dosing and fed 30 min before dosing. Before each dose was administered, blank blood was taken. After intravenous administration, 1 ml of blood was taken through the forelimb vein at 5 min, 15 min, 30 min, 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours, and 24 hours.
  • the method of precipitating protein by acetonitrile was carried out by adding 150 ⁇ l of an internal standard acetonitrile solution to 50 ⁇ l of the plasma sample to be shaken for 2 min, centrifuging at 14,000 rpm for 10 min, then taking 150 ⁇ l of the supernatant, diluting twice with 150 ⁇ l of ultrapure water, and taking 10 ⁇ L of the injection analysis.
  • the drug concentration of the compound of formula A in the biological sample was determined by LC-MS/MS analysis.
  • the instrument is an API4000 triple quadrupole mass spectrometer from Applied Biosystem of the United States and a 1200 series liquid chromatography system from Agilent, Germany.
  • the column was a CAPCELL PAK C 18 column (MG, 50 x 2.0 mm, 5 ⁇ m).
  • ESI electrospray ionization source
  • Kinetica 4.0 American Thermo-Fisher pharmacokinetic software was used for data analysis and pharmacokinetic parameters were calculated using the non-compartment model statistical moment method. C max and T max is found.
  • the average exposure (AUC 0- ⁇ ) in vivo was 714 h ⁇ ng/mL; the terminal phase half-life (t 1/2 ) was 4.12 hours.
  • the average exposure (AUC 0- ⁇ ) in vivo was 228, 1126 and 5424 h ⁇ ng/mL, respectively; the terminal phase half-life after oral administration was 3.22 and 4.20, respectively. And 7.71 hours.
  • the half-life of oral doses of 1 and 2.5 mg/kg was about 4 hours.
  • the blood concentration of the 7.5 mg/kg dose group was slower than that of the 1 and 2.5 mg/kg dose groups. The blood concentration was still 24 hours after administration. More than 50 ng/mL.
  • the oral absolute bioavailability calculated by the mean of the in vivo plasma exposure (AUC 0- ⁇ ) obtained by oral and intravenous injection of the same dose (1 mg/kg) was 30.6 ⁇ 15.0%.
  • Form I Compound I Form I has acceptable oral bioavailability and is suitable for the preparation of oral pharmaceutical preparations.

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Abstract

La présente invention concerne le domaine de la pharmacie et fournit une forme cristalline d'un composé (3aR,6aR)-N-(4-(3-éthynylphénylamino)-7-méthoxyquinazolin-6-yl)-1-méthyl-hexahydropyrrolo[3,4-b]pyrrole-5(1H)-carboxamide, une composition pharmaceutique de celui-ci, et son procédé de préparation et son utilisation.
PCT/CN2017/114194 2016-12-01 2017-12-01 Forme cristalline d'un composé Ceased WO2018099451A1 (fr)

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CN102311438A (zh) * 2010-06-30 2012-01-11 和记黄埔医药（上海）有限公司 喹唑啉化合物
CN102906086A (zh) * 2010-06-30 2013-01-30 和记黄埔医药（上海）有限公司 喹唑啉化合物

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WO2012000182A1 (fr) * 2010-06-30 2012-01-05 Hutchison Medipharma Limited Composés à base de quinazoline

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CN102311438A (zh) * 2010-06-30 2012-01-11 和记黄埔医药（上海）有限公司 喹唑啉化合物
CN102906086A (zh) * 2010-06-30 2013-01-30 和记黄埔医药（上海）有限公司 喹唑啉化合物

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